"The tissue inhibitors of metalloproteinases (TIMP's) are a family of closely related proteins that were initially described as inhibitors of matrix metalloproteinases (MMPs). We have shown that in addition to blocking MMP activity, TIMPs also have growth factor-like activity, promoting growth in B-cells in a manner independent of MMP inhibitory activity. TIMP-1 is expressed by reactive lymphoid cells as well as cell lines derived from B-cell neoplasms. TIMP-1 expression in these cells is unrelated to MMP expression. TIMP-1 expression correlates with differentiation state and appears to be expressed by a specific stage of germinal center B-cells. TIMP-1 induces further differentiation in B-cells to the germinal center phenotype that occurs with the generation of lymphoblasts. TIMP-1 expression also correlates positively with Group II/III EBV latency phenotype. TIMP-1 affects B-cell activation by inducing expression and secretion of the activation marker CD23. TIMP-1 inhibits cold shock, Fas, radiation and serum starvation induced apoptosis without causing withdrawal from cell cycle. TIMP-1 up-regulates the survival antigen CD40 and down-regulates expression of CD77, a neutral glycolipid expressed by a subset of B lymphocytes that readily enter programmed cell death. TIMP-1 up-regulates Bcl-XL but does not affect Bcl-2 or Mcl-1 expression. TIMP-1 also does not modify cytoplasmic levels of NF-kB but does increase expression of the NF-kB inhibitor IkBa. In a study of B-cell non-Hodgkin's lymphomas there was a high degree of correlation between TIMP-1 expression and histologic grade. Interleukin-10 (IL-10) is expressed by non-Hodgkin's lymphomas, where it acts as a cooperative growth factor. TIMP-1 induces IL-10 expression in B-cells in a non-MMP dependent manner. There is a strong correlation between TIMP-1 and IL-10 expression in B-cell NHL. In summary, TIMP-1 induces B-cell differentiation and inhibits PCD by a novel mechanism. Furthermore, TIMP-1 expression may be a negative prognostic factor in non-Hodgkin's lymphoma."